The further a society drifts from the truth, the more it will hate those who speak it. ... In a time of deceit, telling the truth is a revolutionary act. George Orwell

Saturday, June 2, 2012

Unknown keto+glucose oxygen-sparing metabolism?

I came across this in the following papers. May be a false lead, may be not.

"Cerebral metabolic adaptation and ketone metabolism after
brain injury", Mayumi L Prins, 2008

"In vivo 13C NMR studies of compartmentalized cerebral carbohydrate metabolism", Rolf Gruetter, 2002

"Brain Metabolism during Fasting", 0.E.OWEN et al., 1967

The papers review ketone and glucose metabolism in brain tissue. Among many of the issues discussed one finds that at a time of trauma, injury, hypoxia or during birth, brain tissue switches to some unspecified (unknown?) type of metabolism characterised by:
  1. increased processing of glucose through the pentose phosphate pathway (PPP),
  2. increased expression of ketone-metabolizing enzymes,
  3. relative reduction of oxygen use and CO2 release, in comparision with the overall rate of metabolism.
It is important to notice that PPP, as described in the literature is a pure glucose pathway oxydative-reductive (oxygen-sparing as compared with the normal glucose oxidative pathway) that is normally associated with NADPH production, used in reductive biosynthesis reactions within cells (e.g. fatty acid synthesis, RNA, cholesterol etc). Based on the known biochemistry, PPP is not supposed to have anything to do with ketone bodies or fatty acid metabolism in general.

Ketone metabolism on the other hand is not oxygen-sparing at all! A simple stoichometric analysis indicate similar oxygen usage per calorie compared with glucose oxidation (but with a significantly reduced carbon dioxide production!).

It is very hard to reconcile 1 and 2 with 3 unless one postulates that a new yet unnamed metabolic process is taking place that oxidizes ketone bodies and at the same time reduces (i.e. takes oxygen out of) glucose, with PPP being a side effect.  (It cannot be the traditional anaerobic glucose metabolism because of the reported deficit of lactate)

Quotes (first paper):
Although glycolytic activity is 38% greater in adults than fetal brain, the processing of glucose through the pentose phosphate pathway was 164% higher within the fetal brain compared with adults.
Hypoxic injury reduces oxygen availability and thus decreases oxidative glucose metabolism resulting in increased lactate production. High tolerance to hypoxia has been associated with increased plasma ketone levels...
In addition to neuroprotection from seizures, administration of ketones has been shown to provide protection after hypoxia/ischemia (Table 3).

My comment:

- hard to reconcile with the known metabolism of ketones which requires similar amount of oxygen as glucose (per calorie).

Quote (second paper):
The landmark study by Fox and Raichle in the late 1980s suggested that there is indeed a large increase in glucose metabolism that exceeds the changes in oxygen metabolism (Fox et al., 1988). The concept of uncoupled oxygen metabolism has been supported by reports of small increases in brain lactate during focal activation (Prichard et al., 1991), that initially were very controversial (Merboldt et al., 1992) and that are very difficult to perform. The relatively small magnitude of change in brain lactate is difficult to reconcile with the reported large uncoupling between oxygen and glucose consumption (Madsen et al., 1999).
My comment:

- a well known anaerobic (no oxygen) metabolism involves conversion of glucose to lactate, thus the lack of lactate, is the paradox indicating an unknown oxygen-sparing pathway.

Quote (third paper): stated before, 2.81 mmoles/liter of CO2, should have been produced, with a theoretical respiratory quotient of 0.92 instead of the observed 1.90 mmoles/liter, resulting in a quotient of 0.62. To our knowledge, this deficit in CO2 production can only be explained by a carboxylation [see wiki] reaction with the venous effluent transporting the CO2 in a form not liberated by the acidification used in the standard manometric technique for determination of CO2 and HCO3.   According to most observations, the respiratory quotient of brain, which glucose serves as sole energy source, is close to unity (2,3,25). Brain, however, contains enzymes for all the major metabolic pathways (29-31), including fixation of CO2 (31,32); and oxidation of keto acids has been demonstrated in vitro (30,33,34). In addition, Kety et al. (35) noted decreased respiratory quotients in patients in diabetic ketoacidosis; but direct utilization of keto acids has not been found in this condition (3) or in fat-fed animals (36). Guettstein et al. also observed decreased respiratory quotients in patients with cerebral arteriosclerosis (37). Additional indirect evidence for a novel carboxylation reaction which would result in a low quotient has been Sacks' studies on glucose-14C oxidation in human brain whereby only 50% of glucose-carbon that is oxidized is recovered in effluent CO2 and HCO3,(38).

My comment:

Reduction of respiratory quotient to 0.62 meant that the process releases less CO2 than should have been base don the known and expected metabolic pathway. That indicates that the unknown metabolic process does not oxidize carbon to CO2 but leaves it in the residua, while probably (speculating) oxidizing only the hydrogen from ketone bodies with the oxygen atoms reduced from glucose. The result is less need for external oxygen input and less CO2 production. (Mental note: next post about Dr. Jan Kwasniewski!)

(Kudos for Dr. Dav0 for pointing out those papers, and his work on ketone metabolism, please keep it up!)